tbuckley/cabot-search huggingface dataset:
Analysis of COVID-19 Incidence and Severity Among Adults Vaccinated With 2-Dose mRNA COVID-19 or Inactivated SARS-CoV-2 Vaccines With and Without Boosters in Singapore
Authors: Oon Tek Ng, Kalisvar Marimuthu, Nigel Lim, Ze Qin Lim, Natascha May Thevasagayam, Vanessa Koh, Calvin J. Chiew, Stefan Ma, Mingshi Koh, Pin Yan Low, Say Beng Tan, Joses Ho, Sebastian Maurer-Stroh, Vernon J. M. Lee, Yee-Sin Leo, Kelvin Bryan Tan, Alex R. Cook, Chorh Chuan Tan
Journal: JAMA Network Open (2022)

Assessing booster effectiveness of COVID-19 mRNA vaccine and inactivated SARS-CoV-2 vaccine over longer time intervals and in response to any further SARS-CoV-2 variants is crucial in determining optimal COVID-19 vaccination strategies.To determine levels of protection against severe COVID-19 and confirmed SARS-CoV-2 infection by types and combinations of vaccine boosters in Singapore during the Omicron wave.This cohort study included Singapore residents aged 30 years or more vaccinated with either at least 2 doses of mRNA COVID-19 vaccines (ie, Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273) or inactivated SARS-CoV-2 vaccines (Sinovac CoronaVac or Sinopharm BBIBP-CorV) as of March 10, 2022. Individuals with a known SARS-CoV-2 infection prior to December 27, 2021, an infection on or before the date of their second vaccine dose, or with reinfection cases were excluded.Two or 3 doses of Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Sinovac CoronaVac, or Sinopharm BBIBP-CorV.Notified infections from December 27, 2021, to March 10, 2022, adjusted for age, sex, race, housing status, and calendar days. Estimated booster effectiveness, defined as the relative incidence-rate reduction of severe disease (supplemental oxygen, intensive care, or death) or confirmed infection following 3-dose vaccination compared with 5 months after second mRNA dose, was determined using binomial regression.Among 2 441 581 eligible individuals (1 279 047 [52.4%] women, 846 110 (34.7%) aged 60 years and older), there were 319 943 (13.1%) confirmed SARS-CoV-2 infections, of which 1513 (0.4%) were severe COVID-19 cases. mRNA booster effectiveness against confirmed infection 15 to 60 days after boosting was estimated to range from 31.7% to 41.3% for the 4 boosting combinations (homologous BNT162b2, homologous mRNA-1273, 2-dose BNT162b2/mRNA-1273 booster, and 2-dose mRNA-1273/BNT162b2 booster). Five months and more after boosting, estimated booster effectiveness against confirmed infection waned, ranging from -2.8% to 14.6%. Against severe COVID-19, estimated mRNA booster effectiveness was 87.4% (95% CI, 83.3%-90.5%) 15 to 60 days after boosting and 87.2% (95% CI, 84.2%-89.7%) 5 to 6 months after boosting, with no significant difference comparing vaccine combinations. Booster effectiveness against severe COVID-19 15 days to 330 days after 3-dose inactivated COVID-19 vaccination, regardless of combination, was estimated to be 69.6% (95% CI, 48.7%-81.9%).Booster mRNA vaccine protection against severe COVID-19 was estimated to be durable over 6 months. Three-dose inactivated SARS-CoV-2 vaccination provided greater protection than 2-dose but weaker protection compared with 3-dose mRNA.
Examining Access to Digital Technology by Race and Ethnicity and Child Health Status Among Chicago Families
Authors: Kristin Kan, Nia Heard-Garris, Anne Bendelow, Lu Morales, Marquita W. Lewis-Thames, Matthew M. Davis, Marie Heffernan
Journal: JAMA Network Open (2022)

This cross-sectional study characterizes the type and quality of digital access among racially and ethnically as well as socioeconomically diverse households with children in Chicago.
Estimating Risk of Chronic Pain and Disability Following Musculoskeletal Trauma in the United Kingdom
Authors: David W. Evans, Alison Rushton, Nicola Middlebrook, Jon Bishop, Marco Barbero, Jaimin Patel, Deborah Falla
Journal: JAMA Network Open (2022)

Importance Serious traumatic injury is a leading cause of death and disability globally, with most survivors known to develop chronic pain. Objective To describe early variables associated with poor long-term outcome for posttrauma pain and create a clinical screening tool for this purpose. Design, Setting, and Participants This was a prospective cohort study at a major trauma center hospital in England. Recruitment commenced in December 2018 and ceased in March 2020. Participants were followed up for 12 months. Patients aged 16 years or older who were hospitalized because of acute musculoskeletal trauma within the preceding 14 days were included. Data were analyzed from March to December 2021. Exposure Acute musculoskeletal trauma requiring admittance to a major trauma center hospital. Main Outcomes and Measures A poor outcome was defined as Chronic Pain Grade II or higher and measured at both 6 months (primary time point) and 12 months. A broad range of candidate variables potentially associated with outcomes were used, including surrogates for pain mechanisms, quantitative sensory testing, and psychosocial factors. Univariable models were used to identify the variables most likely to be associated with poor outcome, which were entered into multivariable models. A clinical screening tool (nomogram) was derived from 6-month results. Results In total, 1590 consecutive patients were assessed for eligibility, of whom 772 were deemed eligible and 124 (80 male [64.5%]; mean [SD] age, 48.9 [18.8] years) were recruited. At 6 months, 19 of 82 respondents (23.2%) reported a good outcome, whereas at 12 months 27 of 44 respondents (61.4%) reported a good outcome. At 6 months on univariable analysis, an increase in total posttraumatic stress symptoms (odds ratio [OR], 2.09; 95% CI, 1.33-3.28), pain intensity average (OR, 2.87; 95% CI, 1.37-6.00), number of fractures (OR, 2.79; 95% CI, 1.02-7.64), and pain extent (OR, 4.67; 95% CI, 1.57-13.87) were associated with worse outcomes. A multivariable model including those variables had a sensitivity of 0.93, a specificity of 0.54, and C-index of 0.92. Conclusions and Relevance A poor long-term pain outcome from musculoskeletal traumatic injuries may be estimated by measures recorded within days of injury. These findings suggest that posttraumatic stress symptoms, pain spatial distribution, perceived average pain intensity, and number of fractures are good candidates for a sensitive multivariable model and derived clinical screening tool.
Geographic and Racial Disparities in Access to Chimeric Antigen Receptor–T Cells and Bispecific Antibodies Trials for Multiple Myeloma
Authors: Raghad Alqazaqi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, John Shaughnessy, Fenghuang Zhan, Guido Tricot, Frits van Rhee, Samer Al Hadidi
Journal: JAMA Network Open (2022)

The use of chimeric antigen receptor-T cell (CAR-T) therapy and bispecific antibodies in multiple myeloma is expanding, with encouraging early results. It is unknown if the current geographic distribution of CAR-T therapy and bispecific antibodies in multiple myeloma allows access for patients in need, especially for Black populations, which have a higher incidence of multiple myeloma.To investigate if the current geographic distribution of CAR-T cell therapy and bispecific antibodies for multiple myeloma allows equitable access for Black patients with multiple myeloma.This cross-sectional study of data from CAR-T therapy and bispecific antibodies multiple myeloma clinical trials for all available studies listed in ClinicalTrials.gov until January 31, 2022. Only studies with 1 or more open sites in the US were analyzed. Data were analyzed February 2022.A total of 162 clinical trials were found, and 69 analyzed-7896 participants were either enrolled or expected to enroll, with 4386 participants (55.5%) enrolled or to be enrolled in CAR-T therapies clinical trials. The vast majority of clinical trials (66 [96%]) were sponsored by industry, and there were 140 clinical trials sites. The mean number of sites per trial was 8.1 (7.8 for CAR-T trials [range, 1-30 trials] vs 8.7 for bispecific antibodies [range, 1-26 trials]). Only 35.9% of Black patients lived in a county with an open trial. For the 10 states with the highest proportion of Black residents (ranging from 18.6% to 41.4%), 6 of those states (60%) had no (3 states) or less than 3 clinical trial openings (3 states) for either a CAR-T or bispecific antibody study.In this cross-sectional study, we found that the geographic distribution of clinical trials for CAR-T and bispecific antibodies may contribute to disparities in access to the most advanced clinical trials for new multiple myeloma therapies. Since most of the ongoing trials were sponsored by industry, regulating the distribution of clinical trial sites may reduce these inequities.
When I use a word . . . . Too much healthcare—technology
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

Much modern healthcare depends on the excellent technology that we have at our disposal. However, technology can result in too much healthcare, not by having too much technology, but because the technology we have is capable of being misused or the results misinterpreted. New forms of technology are often associated with fear: fear of using them lest damage occurs, either to the technology itself or through use of the technology, and fear of "technological unemployment." Artificial intelligence can go wrong through unintended consequences of the programming. Technology can be deliberately misused, as when predatory open access journals offer online publication of poor research for payment, without offering the type of backup that one would normally expect from a publisher, or when machine translators are used to substitute terms in fake papers with so-called "tortured phrases." Producing fake images through manipulation is another example. Misinterpretation of technological outputs can also lead to impaired healthcare. Technological advances have revolutionised our management of many healthcare problems, but misuse of technology and misinterpretation of results can lead to overdetection, overdiagnosis, and misdiagnosis, potentially leading to overtreatment.
Modeling the Impact of Sexual Networks in the Transmission of <i>Monkeypox virus</i> Among Gay, Bisexual, and Other Men Who Have Sex with Men — United States, 2022
Authors: Ian H. Spicknall, Emily D. Pollock, Patrick A. Clay, Alexandra M. Oster, Kelly Charniga, Nina Masters, Yoshinori J. Nakazawa, Gabriel Rainisch, Adi V. Gundlapalli, Thomas L. Gift
Journal: MMWR Morbidity and Mortality Weekly Report (2022)
Rates of Medical Student Placement Into Graduate Medical Education by Sex, Race and Ethnicity, and Socioeconomic Status, 2018-2021
Authors: Mytien Nguyen, Sarwat I. Chaudhry, Mayur M. Desai, Alexandra M. Hajduk, William A. McDade, Tonya L. Fancher, Dowin Boatright
Journal: JAMA Network Open (2022)

This cohort study investigates whether different rates of medical student placement into graduate medical education exist by sex, race and ethnicity, and socioeconomic status from 2018 to 2021.
Transcriptional Profiling Identifies Gene Expression Changes Associated with IFN-α Tolerance in Hepatitis C–Related Hepatocellular Carcinoma Cells
Authors: Nathalie Wong, Kathy Y-Y. Chan, Pascale F. Macgregor, Paul B-S. Lai, Jeremy A. Squire, Ben Beheshti, Monique Albert, Thomas W-T. Leung
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Treatment with IFN-α therapy has been shown to exhibit antitumor effects on patients with hepatocellular carcinoma (HCC). However, individual responses remained unpredictable because of the frequent presence of intrinsic or acquired IFN-α resistance. Hence, delineation of molecular targets implicated in the resistant pathway holds value in refining the therapeutic benefits of IFN-α. Experimental Design: The current study analyzed the effect of IFN-α in human HCC cells. Three hepatitis C virus (HCV)–related, five hepatitis B virus (HBV)–related and two non-B non-C–related cell lines were subjected to IFN-α treatment and the cytotoxic effect on cell viability was measured. Further analysis by cDNA microarray and quantitative reverse transcription-PCR were conducted to examine the gene expression changes that mediated the IFN-α resistance observed. Results: According to the IC50 values determined, HCV-related cell lines indicated distinct resistance (IC50, 389-1468 units/mL) compared with the HBV-related (IC50, 11-77 units/mL) and non-B non-C–related cell lines (IC50, 24-108 units/mL). Unsupervised hierarchical clustering on array data indicated three HCV-related cell lines to cluster independently from the sensitive cell lines, suggesting discrete features in association with IFN-α tolerance. Moreover, Significance Analysis of Microarrays analysis indicated the differential expression of 149 expressed sequence tags that represented 51 up-regulated and 98 down-regulated genes in the resistant cell lines. Comparing the temporal pattern of gene expression between 6- and 24-hour treatments, candidate genes that were considerably induced with time were further highlighted in the tolerant HCV-related cell lines. These candidates were verified by quantitative reverse transcription-PCR, which confirmed the down-regulation of UBA2, ZNF185, and FOXF1 and up-regulation of UBE4B in the drug-tolerant cells. Conclusions: Our present study showed that the insensitivity to IFN-α therapy in HCC cells is associated with drug-inducible transcriptional alterations. Furthermore, our investigation highlighted potential candidate genes in conferring an anti-apoptotic effect toward IFN-α treatment.
Loss of the AP-2α Transcription Factor Is Associated with the Grade of Human Gliomas
Authors: Amy B. Heimberger, Eric C. McGary, Dima Suki, Maribelis Ruiz, Huamin Wang, Gregory N. Fuller, Menashe Bar-Eli
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The activator protein (AP)-2α transcription factor plays a crucial role in the progression of several human tumors, including malignant melanoma, prostate, and breast cancer. Loss of AP-2α results in deregulation of several genes with AP-2α binding motifs such as E-cadherin, p21WAF1, MMP-2, MCAM/MUC18, VEGF, and c-KIT. The purpose of our study was to determine AP-2α expression distribution among grades of gliomas and any possible effect on prognosis. Experimental Design: A tissue microarray was assembled from all surgical glioma cases with available tissue samples at M.D. Anderson Cancer Center since 1986 to include 72 glioblastomas, 49 anaplastic astrocytomas, 9 low-grade astrocytoma, 37 oligodendrogliomas, 37 anaplastic oligodendrogliomas, 15 mixed oligoastrocytomas, 20 anaplastic mixed oligoastrocytomas, and 7 gliosarcomas. The microarray included normal brain tissue, and AP-2α expression was determined by immunohistochemistry. Results: AP-2α expression was lost on 99% (P &amp;lt; 0.001) and 98% (P &amp;lt; 0.001) of glioblastomas and anaplastic astrocytomas, respectively, compared with grade 2 astrocytomas and normal brain, all of which (100%) maintained expression of AP-2α. The loss of AP-2α was a negative prognostic indicator within the overall category of gliomas by univariate analysis (rate ratio, 4.30; 95% confidence interval, 2.60-7.10; P &amp;lt; 0.001). However, there was no significant effect of loss of AP-2α expression on survival observed after adjustment for patient age, Karnofsky Performance Scale score, tumor grade, and extent of resection (rate ratio, 1.2; 95% confidence interval, 0.6-2.2; P = 0.6). Conclusions: AP-2α expression correlates inversely with glioma grade, suggesting a direct role in glioma tumorigenicity, possibly through subsequent deregulation of target genes. Of all the previously characterized markers of progression, the loss of AP-2α would be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.
Polymorphisms in <i>ER</i>-α Gene Interact with Estrogen Receptor Status in Breast Cancer Survival
Authors: Sonia M. Boyapati, Xiao Ou Shu, Zhi Xian Ruan, Qiuyin Cai, Jeffrey R. Smith, Wanqing Wen, Yu-Tang Gao, Wei Zheng
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The effects of estrogens are mediated primarily through estrogen receptor (ER) in breast tissue, and polymorphisms in the ER genes may alter the functions of these receptors. Polymorphisms in the ER-α gene have been reported to be associated with breast cancer risk. However, to our knowledge, no study has been published on the relation between ER-α gene polymorphisms and breast cancer survival. Experimental Design: To determine whether three common polymorphisms in the ER-α gene, PvuII, XbaI, and GT dinucleotide repeats are associated with breast cancer survival, we evaluated data from a cohort of 1,069 breast cancer patients who participated in the Shanghai Breast Cancer Study between 1996 and 1998. The median follow-up time for this cohort of women was 5.2 years. Results: No overall association was observed between ER gene polymorphisms and breast cancer survival. The genotype associations, however, were modified by ER status in breast cancer tissues. Comparing those with the PP genotype to the pp genotype of the PvuII polymorphism, the hazard ratios (HR) of dying were 3.30 [95% confidence interval (95% CI), 1.42-7.69] and 0.54 (95% CI, 0.24-1.23), respectively, for participants with ER-negative breast cancer and ER-positive breast cancer. Similarly, compared with those with no (GT)23 alleles, carrying one or two (GT)23 alleles of the GT repeat polymorphism was related to a HR of 1.48 (95% CI, 0.77-2.87) for ER-negative breast cancer and a HR of 0.25 (95% CI, 0.09-0.69) for ER-positive cancer. The effect of ER on breast cancer survival was also modified by genotypes of ER-α gene. Tests for multiplicative interaction were highly significant. Conclusions: These data suggest that the ER-α gene polymorphisms and ER status may have an interactive effect on breast cancer survival.
Interferon regulatory factor 1‐triggered free ubiquitin protects the intestines against radiation‐induced injury via CXCR4/FGF2 signaling
Authors: Yang Jiao, Jing Xu, Bin Song, Ailing Wu, Lu Pan, Ying Xu, Fenghao Geng, Xiaoqian Li, Congzhao Zhao, Min Hong, Xuanyu Meng, Judong Luo, Pengfei Liu, Ming Li, Wei Zhu, Jianping Cao, Shuyu Zhang
Journal: MedComm (2022)

Radiation-induced intestinal injury is a serious concern during abdominal and pelvic cancers radiotherapy. Ubiquitin (Ub) is a highly conserved protein found in all eukaryotic cells. This study aims to explore the role and mechanism of free Ub against radiogenic intestinal injury. We found that free Ub levels of irradiated animals and human patients receiving radiotherapy were upregulated. Radiation-induced Ub expression was associated with the activation of interferon regulatory factor 1 (IRF1). Intraperitoneal injection of free Ub significantly reduced the mortality of mice following 5-9 Gy total body irradiation (TBI) through the Akt pathway. Free Ub facilitates small intestinal regeneration induced by TBI or abdominal irradiation. At the cellular level, free Ub or its mutants significantly alleviated cell death and enhanced the survival of irradiated intestinal epithelial cells. The radioprotective role of free Ub depends on its receptor CXCR4. Mechanistically, free Ub increased fibroblast growth factor-2 (FGF2) secretion and consequently activated FGFR1 signaling following radiation in vivo and in vivo. Thus, free Ub confers protection against radiation-induced intestinal injury through CXCR4/Akt/FGF2 axis, which provides a novel therapeutic option.
Changes in Bone Marrow Tumor and Immune Cells Correlate with Durability of Remissions Following BCMA CAR T Therapy in Myeloma
Authors: Kavita M. Dhodapkar, Adam D. Cohen, Akhilesh Kaushal, Alfred L. Garfall, Renee Julia Manalo, Allison R. Carr, Samuel S. McCachren, Edward A. Stadtmauer, Simon F. Lacey, J. Joseph Melenhorst, Carl H. June, Michael C. Milone, Madhav V. Dhodapkar
Journal: Blood Cancer Discovery (2022)

Chimeric antigen-receptor (CAR) T cells lead to high response rates in myeloma, but most patients experience recurrent disease. We combined several high-dimensional approaches to study tumor/immune cells in the tumor microenvironment (TME) of myeloma patients pre- and post-B-cell maturation antigen (BCMA)-specific CAR T therapy. Lower diversity of pretherapy T-cell receptor (TCR) repertoire, presence of hyperexpanded clones with exhaustion phenotype, and BAFF+PD-L1+ myeloid cells in the marrow correlated with shorter progression-free survival (PFS) following CAR T therapy. In contrast, longer PFS was associated with an increased proportion of CLEC9A+ dendritic cells (DC), CD27+TCF1+ T cells with diverse T-cell receptors, and emergence of T cells expressing marrow-residence genes. Residual tumor cells at initial response express stemlike genes, and tumor recurrence was associated with the emergence of new dominant clones. These data illustrate a dynamic interplay between endogenous T, CAR T, myeloid/DC, and tumor compartments that affects the durability of response following CAR T therapy in myeloma.There is an unmet need to identify determinants of durable responses following BCMA CAR T therapy of myeloma. High-dimensional analysis of the TME was performed to identify features of immune and tumor cells that correlate with survival and suggest several strategies to improve outcomes following CAR T therapy. See related commentary by Graham and Maus, p. 478. This article is highlighted in the In This Issue feature, p. 476.
Herstatin, an Autoinhibitor of the Epidermal Growth Factor (EGF) Receptor Family, Blocks the Intracranial Growth of Glioblastoma
Authors: Julia A. Staverosky, Leslie L. Muldoon, Shuhua Guo, Adam J. Evans, Edward A. Neuwelt, Gail M. Clinton
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Herstatin, an autoinhibitor of the epidermal growth factor (EGF) receptor family, was evaluated for efficacy against human glioblastoma in vitro and in vivo in a rat intracranial model. Experimental Design: Glioblastoma controlled by EGF receptor (EGFR; U87MG) or by the truncated mutant, ΔEGFR (U87MG/Δ), were transfected with Herstatin and evaluated for in vitro and in vivo growth in nude rat brain. Cells treated with purified Herstatin in vitro were evaluated for growth and signal transduction. Results: Herstatin expression prevented tumor formation by U87MG and purified Herstatin inhibited their growth in vitro in a dose-responsive fashion, whereas in vivo and in vitro growth of U87MG/Δ was resistant to Herstatin. Inhibition of U87MG growth correlated with suppressed EGF activation of EGFR and of Akt but not mitogen-activated protein kinase signaling pathways, whereas ΔEGFR activity and intracellular signaling in U87MG/Δ were unaffected by Herstatin treatment. Conclusions: Herstatin may have utility against glioblastoma driven by the EGFR but not the mutant ΔEGFR. Blockade of Akt but not the mitogen-activated protein kinase signaling cascade appears to be critical for suppression of intracranial tumor growth.